Studies On Synthesis And Bioactivity Of Polymethoxyfavones Carboxylic Acid And Amino Acid Derivatives

Polymethoxyflavonoids?PMFs?is a class of liposoluble,relatively low-polarity and highly methoxylated flavonoids that generally exhibits a wide range of biological activities including anti-carcinogenicity,anti-inflammatory,anti-tumor activity and so on.Polymethoxyflavonoids usually do not contain carboxyl groups.Carboxyl group is an important hydrophilic group,the introduction of carboxyl groups into Polymethoxyflavonoids can increase their water solubility,improve the bioactivity and they can be easily absorbed by the human body.Thus,the drug efficacy,the biological activity and the application range of the Polymethoxyflavonoids can be improved.Amino acids are the most basic substances that make up a living body protein and have strong hydrophilicity,good affinity,and special physiological properties in antibodies.Amino acids have been found that when the active molecule is linked to an amino acid,it is more easily taken up by tum or cells,and the selectivity for tumor cells is enhanced,and the solubility and anti-tumor activity of the drug are also improved.After consulting a large amount of literature and combining the research work of the laboratory,This paper synthesized eig ht kinds of polymethoxyflavones Carboxylic acid derivatives and sixteen species of polymethoxyflavones amino acid derivatives at low cost and relatively simple method,Which based on tangerine and nobiletin as raw materials,furthermore,their biological activities were evaluated.1.3-Hydroxytangeretin?1?and 3-Hydroxynobiletin?2?were obtained from the DMDO oxidation reaction and 5-Hydroxytangeretin?3?and 5-Hydroxynobiletein?4?were obtained by selective demethylation reaction,used tangeretin and nobiletin as raw materials.With anhydrous potassium carbonate in DMF,compounds 1,2,3,4were reacted by Williamson synthesis reaction,and finally the pH of the reaction solution is strictly controlled at room temperature for hydrolysis to obtain eight k inds of polymethoxyflavones carboxylic acid derivatives 9¹6 that have not been reported in the literature.2.Under the conditions of dichloromethane as solvent,EDCI and DMAP as the catalytic system,eight kinds of tangerine and nobiletin carboxylic acid derivatives were reacted with glycine methyl ester hydrochloride and phenylalanine methyl ester hydrochloride respectively to obtained sixteen kinds of polymethoxyflavones amino acid methyl ester derivatives.Then amino acid derivatives of tangeretin and nobiletin33⁴8 were obtained by hydrolysis.Sixteen unknown polymethoxylated amino acid derivatives were obtained in the reaction.3.The polymethoxyflavones acid derivative 13 was selected as the representative,and was tested for aminopeptidase,acetylcholine and lipase inhibitory activity,respectively.The test results show that the polymethoxyflavones carboxylic acid derivative 13 is better than that of aminopeptidase and acetylcholine in the inhibitory activity against lipase,when the concentration of the solution is about 30?mol/L.The method of CCK-8 was used to measure the proliferative activity of polymethoxyflavones carboxylic acid derivatives 11,15,16 and polymethoxyflavones amino acid derivatives 43,47,48 against cervical cancer Hela cell s in vitro.The test results showed that the anti-proliferative activity of the polymethoxyflavones amino acid derivatives 43,47 and 48 on Hela cells was better,which was enhanced compared to the intermediate compounds 11,15 and 16.4.A total of 24 polymethoxyflavones carboxylic acids and amino acid derivatives have been synthesized in this paper,and none of them have been reported in the literature.The structures of the synthesized compounds have all been confirmed by ¹H NMR,¹³C NMR and MS/HRMS.